Table of Contents

INTRODUCTION ………………………………………………………………………………………….. 1
Features of Obsessive-Compulsive Disorder ……………………………………………… 1
Approaches to Studying OCD Genetics …………………………………………………….. 2
Association Studies …………………………………………………………………………. 3
Rare Variation in Psychiatric Disease ………………………………………………. 4
Linkage Studies of Rare Inherited Variants ………………………………………… 4
De Novo Variation ………………………………………………………………………….. 5
Post-Zygotic Variants ……………………………………………………………………… 5
Structural (Copy Number) Variation …………………………………………………. 7
Preliminary Studies …………………………………………………………………………………. 8
Statement of Purpose and Specific Aims …………………………………………………. 11
Aim 1: Characterize the Contribution of PZVs to OCD ……………………… 11
Aim 2: Characterize the Contribution of CNVs to OCD …………………….. 12
Aim 3: Identify New OCD Risk Genes and Biological Pathways …………. 12
MATERIALS AND METHODS ……………………………………………………………………… 13
Data collection and processing ………………………………………………………………… 13
Variant Calling ………………………………………………………………………………………. 14
PZV Calling with MosaicHunter …………………………………………………….. 16
CNV Calling with XHMM ………………………………………………………………. 17
Burden Analysis …………………………………………………………………………………….. 18
Mutation Rates of PZVs …………………………………………………………………. 18
Rates of CNVs ………………………………………………………………………………. 19
Exploratory Risk Gene Pathway, and Expression Analyses ……………………… 19
RESULTS …………………………………………………………………………………………………….. 20
Mutation Rates and Burden Analysis ……………………………………………………… 20
PZV Rates…………………………………………………………………………………….. 20
CNV Rates ……………………………………………………………………………………. 23
Pathway Analysis …………………………………………………………………………………… 29
Clinical Features of Notable Cases ………………………………………………………….. 31
Expression Analysis ……………………………………………………………………………….. 32
DISCUSSION ……………………………………………………………………………………………….. 33
Future Directions …………………………………………………………………………………… 36
SUPPLEMENTARY METHODS ……………………………………………………………………. 38
Sequence Alignment……………………………………………………………………………….. 38
Power Calculations ………………………………………………………………………………… 38
Callable Bases ………………………………………………………………………………………… 40
REFERENCES ……………………………………………………………………………………………… 42